In this project we are taking a multifaceted approach to studying molecular basis of programmed cell death in lymphocytes. Our attack is based on the hypothesis that there are principally two mechanisms of programmed death of T cells: i) lymphokine deprivation death (LDD) and ii) propriocidal death (PD) due to antigen stimulation of activated T cells. With regard to LDD, we are trying to understand how withdrawal of a trophic stimulus, IL-2 in the case of T cells, can initiate the death program. We have found that lymphokine withdrawal leads to the activation of the c-jun N-terminal kinase (JNK) pathway and we conjecture that this leads to a gene activation event that initiates the death program. In studying PD, we have focused on the activation of a protease termed Flice/Mach1 (caspase 8) which can directly carry out the death program.